Ventricualr tachucardias which may occur during chronic ischemic heart disease are often resistant to drug therapy, as many times anriarrhythmic drug therapy fails to correct these thythm disorders. The aims of the pressent proposal, which are an integral part of the long term objectives of our laboratory are first to determine the mechanism of such resistance to these potentially lethal rhythm disorders. Specifically we will test two hypotheses. First, resistance of ventricular tachycardia to drugs occurs because of inadequate and deficient delivery of drugs to the site of the arrhythmia. This hypothesis stems from the observations that the site of origin of the arrhythmia reside in the territory of the occluded vessel, where blood flow and drug delivery are limited. Second, resistance of the arrhythmia to drugs is caused because of inadequate antiarrhythmic efficacy of the drug itself. These two hypotheses, which are not mutually exclusive, will be tested on canine models of ischemic arrhythmias caused by coronary artery occlusion that we have developed. The site of origin if ventricular tachycardia will be determined by computer-assisted mapping techniques. Regional myocardial drug distribution and binding will be determined by new immunohistochemical techniques that we are developing and regional myocardial drug concentration will be measured by established biochemical assay techniques. Interventions designed to enhance drug delivery to the site of origin of the arrhythmia will consist if administering the drug through 1) intracoronary route, administered at a point just distal to the site of occlusion, 2) coronary venous retroperfusions systems and, 3) coronary artery reperfusion by release of the occlusive device. The influence of these interventions on regional myocardial electrophysiologic properties (conduction, excitability, refractoriness) and on ventricular tachycardia in the intact dog will then be evaluated. The results of the present study could have important clinical significance, since it has been demonstrated that ventricular arrhythmias in patients with myocardial infarction constitute independent predictors of sudden death and that their effective control with drugs, if possible, could significantly reduce mortality.